The most common pulmonary morbidity of preterm infants is bronchopulmonary dysplasia (BPD). We hypothesize that the initiation of breathing and adaptation of the transitional preterm lung can initiate or propagate a progressive lung injury resulting in BPD. There is almost no information about resuscitation mediated lung injury or guidelines for resuscitation of the preterm despite the ease with which the preterm lung can be injured. We submit a translational research project to perform a factorial assessment of the components of neonatal resuscitation (stretch from high tidal volume and no positive end expiratory pressure, 100% O2, and cold/dry gas) that are likely to injure the preterm lung. In Specific Aim 1 we will expose the fetal preterm lamb lung to the resuscitation intervention and evaluate the injury caused by that intervention alone and evaluate if subsequent ventilation for 3h causes amplification of the injury. In Specific Aim 2 we will use antagonists of NFkappaB, IL-1, IL-8 and CD-18 to define the pathways by which stretch injures the preterm lung. Blockade of the injury may allow us to develop therapeutic strategies for decreasing lung injury in the preterm infant. The majority of infants with birth weights <1 kg have been exposed to chorioamnionitis, which causes lung inflammation and alters innate inflammatory responses. In Specific Aim 3 we will use fetal lambs chronically colonized with Ureaplasma parvum to explore how the chronically inflamed fetal lung responds to resuscitation injury. These studies will provide information for recommendations for resuscitation of the preterm human based on studies that are not possible in the human. Relevance to Public Health: There are no studies or guidelines about how to resuscitate the preterm to avoid lung injury. We will identify the components of resuscitation (stretch, oxygen, cold/dry gas) that may injure the preterm lung, evaluate how the injury develops and how chronic inflammation alters the lung responses. This translational research should result in changes in resuscitation procedures for preterm infants.